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Clinical Trial Results:
Phase III confirmatory efficacy and safety trial of remimazolam (CNS7056) compared with propofol for intravenous anaesthesia during elective surgery

Summary
EudraCT number	2018-000174-29
Trial protocol	DE BE GB NL FR IT
Global end of trial date	02 Apr 2020

Results information
Results version number	v1(current)
This version publication date	22 May 2022
First version publication date	22 May 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CNS7056-022

ISRCTN number

US NCT number

NCT03661489

WHO universal trial number (UTN)

Sponsor organisation name

PAION UK Ltd.

Sponsor organisation address

Kew Road 5, Parkshot House, Unit 302, Richmond, United Kingdom, TW9 2 PR

Public contact

Clinical Trial Information, PAION UK Ltd., +49 2414453101, info@paion.com

Scientific contact

Clinical Trial Information, PAION UK Ltd., +49 2414453101, info@paion.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

05 Nov 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Apr 2020

Global end of trial reached?

Yes

Global end of trial date

02 Apr 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

This was a confirmatory trial to establish non-inferior efficacy and superior safety of remimazolam compared with propofol for induction and maintenance of general anaesthesia for the purpose of elective surgery in ASA class III/IV patients

Protection of trial subjects

This trial was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines

Background therapy

Elective surgical procedure

Evidence for comparator

The comparator used was propofol which is the standard of care in intravenous general anaesthesia

Actual start date of recruitment

22 Jul 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Switzerland: 77

Country: Number of subjects enrolled

Italy: 26

Country: Number of subjects enrolled

Netherlands: 46

Country: Number of subjects enrolled

United Kingdom: 40

Country: Number of subjects enrolled

Belgium: 52

Country: Number of subjects enrolled

Germany: 154

Worldwide total number of subjects

409

EEA total number of subjects

332

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

118

From 65 to 84 years

275

85 years and over

Subject disposition

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Recruitment details

ASA class III/IV patients undergoing elective surgery with the need for general anaesthesia. Further criteria for inclusion and exclusion were specified in the protocol.

Screening details

After obtaining informed consent, patients were screened between Day -28 to Day -1 prior to the day of the elective surgery

Number of subjects started

409

Number of subjects completed

409

Period 1 title

Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Blinding implementation details

Patients were not informed about their assignment to remimazolam or propofol. Investigators were informed about the assignment of each patient to either propofol or remimazolam. The first 2 patients of each trial centre were not assigned to remimazolam or propofol by chance/randomization, but by pre-defined sequence, i.e. 1st patient was assigned to propofol and the 2nd patient assigned to remimazolam. This allowed site teams to learn the study procedures prior to the first use of remimazolam.

Are arms mutually exclusive

Yes

Propofol

Arm description

Total intravenous general anaesthesia induced and maintained with the combination of propofol and remifentanil

Arm type

Active comparator

Investigational medicinal product name

Propofol 2% liquid emulsion in 50 mL vials containing 1 g propofol

Investigational medicinal product code

N01AX10

Other name

Pharmaceutical forms

Emulsion for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous administration. 30 mg/kg/h from t= 00 minutes until t = 03 minutes. 10 mg/kg/h from t = 03 minutes until t = 10 minutes. 0. 8 mg/kg/h from t = 10 minutes until t = 20 minutes. 6 mg/kg/h from t = 20 minutes onwards. After t = 20 minutes, titration according to each patient's individual needs was allowed in a range between 4 mg/kg/h an 10 mg/kg/h. Up to 3 boluses of 30 mg/kg/h within 60 minutes were allowed. If the Narcotrend index was below 27 under the lowest allowed dosage of remifentanil, it was allowed to stop the administration of propofol completely.

Remimazolam

Arm description

Total intravenous general anaesthesia induced and maintained with the combination of remimazolam and remifentanil.

Arm type

Experimental

Investigational medicinal product name

Remimazolam

Investigational medicinal product code

N05CD14

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous administration. 6.0 mg/min from t = 00 minutes until t = 03 minutes. 2.5 mg/min from t = 03 minutes until t = 10 minutes. 1.5 mg/min from t = 10 minutes until t = 20 minutes. After t = 20 minutes, titration according to each patient's individual needs was allowed in a range between 0.7 and 2.5 mg/min. Up to 3 bolues of 6 mg/min for 1 minute were allowed within 60 minutes.If the Narcotrend index was below 27 under the lowest allowed dosage of remifentanil, it was allowed to stop the administration of remimazolam completely. Remimazolam was dosed independent from body weight.

Number of subjects in period 1	Propofol	Remimazolam
Started	118	291
Completed	118	288
Not completed	0	3
Immediate re-operation required	-	1
OP cancelled after induction of anaesthesia	-	1
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Propofol

Reporting group description

Total intravenous general anaesthesia induced and maintained with the combination of propofol and remifentanil

Reporting group title

Remimazolam

Reporting group description

Total intravenous general anaesthesia induced and maintained with the combination of remimazolam and remifentanil.

Reporting group values	Propofol	Remimazolam	Total
Number of subjects	118	291	409
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	37	81	118
From 65-84 years	75	200	275
85 years and over	6	10	16
Age continuous
Units: years
arithmetic mean (standard deviation)	68.13 ( 10.809 )	68.63 ( 10.677 )	-
Gender categorical
The gender was not specified for one patient
Units: Subjects
Female	34	82	116
Male	84	209	293
ASA class III/IV patients
Units: Subjects
ASA III	111	278	389
ASA IV	7	13	20

Subject analysis set title

Safety Set, Remimazolam, Final Analysis

Subject analysis set type

Safety analysis

Subject analysis set description

All patients at the final analysis who received any amount of remimazolam

Subject analysis set title

Safety Set, Propofol, Final Analysis

Subject analysis set type

Safety analysis

Subject analysis set description

All patients at the final analysis who received any amount of propofol

Subject analysis set title

Full Analysis Set, Remimazolam, Interim Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the interim analysis who were administered remimazolam over 1 minute or longer

Subject analysis set title

Full Analysis Set, Propofol, Interim Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the interim analysis who were administered propofol over 1 minute or longer

Subject analysis set title

Per Protocol Set 1, Remimazolam, Interim Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the interim analysis who were administered remimazolam over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint

Subject analysis set title

Per Protocol Set 1, Propofol, Interim Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the interim analysis who were administered propofol over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint

Subject analysis set title

Full Analysis Set, Remimazolam, Final Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the final analysis who were administered remimazolam over 1 minute or longer

Subject analysis set title

Full Analysis Set, Propofol, Final Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the final analysis analysis who were administered propofol over 1 minute or longer

Subject analysis set title

Per Protocol Set 1, Remimazolam, Final Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the final analysis who were administered remimazolam over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint

Subject analysis set title

Per Protocol Set 1, Propofol, Final Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the final analysis who were administered propofol over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint.

Subject analysis set title

Full Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Set including both treatment groups

Subject analysis sets values	Safety Set, Remimazolam, Final Analysis	Safety Set, Propofol, Final Analysis	Full Analysis Set, Remimazolam, Interim Analysis	Full Analysis Set, Propofol, Interim Analysis	Per Protocol Set 1, Remimazolam, Interim Analysis	Per Protocol Set 1, Propofol, Interim Analysis	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis	Per Protocol Set 1, Remimazolam, Final Analysis	Per Protocol Set 1, Propofol, Final Analysis	Full Safety Set
Number of subjects	291	118	191	63	165	60	270	95	235	92	409
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	81	37	57	21	46	20	78	30	62	29	118
From 65-84 years	200	75	127	38	114	36	183	60	166	58	275
85 years and over	10	6	7	4	5	4	9	5	7	5	16
Age continuous
Units: years
arithmetic mean (standard deviation)	68.63 ( 10.677 )	68.13 ( 10.809 )	67.90 ( 11.551 )	67.40 ( 10.495 )	( )	( )	68.32 ( 10.833 )	68.28 ( 10.208 )	69.08 ( 10.115 )	68.22 ( 10.268 )	68.49 ( 10.705 )
Gender categorical
The gender was not specified for one patient
Units: Subjects
Female	82	34	62	15			75	25			292
Male	209	83	129	48			195	70			116
ASA class III/IV patients
Units: Subjects
ASA III	278	111	180	59	154	56	258	89
ASA IV	13	7	11	4	11	4	12	6

End points

Top of page

Reporting group title

Propofol

Reporting group description

Total intravenous general anaesthesia induced and maintained with the combination of propofol and remifentanil

Reporting group title

Remimazolam

Reporting group description

Total intravenous general anaesthesia induced and maintained with the combination of remimazolam and remifentanil.

Subject analysis set title

Safety Set, Remimazolam, Final Analysis

Subject analysis set type

Safety analysis

Subject analysis set description

All patients at the final analysis who received any amount of remimazolam

Subject analysis set title

Safety Set, Propofol, Final Analysis

Subject analysis set type

Safety analysis

Subject analysis set description

All patients at the final analysis who received any amount of propofol

Subject analysis set title

Full Analysis Set, Remimazolam, Interim Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the interim analysis who were administered remimazolam over 1 minute or longer

Subject analysis set title

Full Analysis Set, Propofol, Interim Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the interim analysis who were administered propofol over 1 minute or longer

Subject analysis set title

Per Protocol Set 1, Remimazolam, Interim Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the interim analysis who were administered remimazolam over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint

Subject analysis set title

Per Protocol Set 1, Propofol, Interim Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the interim analysis who were administered propofol over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint

Subject analysis set title

Full Analysis Set, Remimazolam, Final Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the final analysis who were administered remimazolam over 1 minute or longer

Subject analysis set title

Full Analysis Set, Propofol, Final Analysis

Subject analysis set type

Full analysis

Subject analysis set description

All patients at the final analysis analysis who were administered propofol over 1 minute or longer

Subject analysis set title

Per Protocol Set 1, Remimazolam, Final Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the final analysis who were administered remimazolam over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint

Subject analysis set title

Per Protocol Set 1, Propofol, Final Analysis

Subject analysis set type

Per protocol

Subject analysis set description

All patients at the final analysis who were administered propofol over 1 minute or longer and who had no major protocol deviations preventing the accurate evaluation of the primary endpoint.

Subject analysis set title

Full Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Set including both treatment groups

Primary: The percentage (%) of time of NCI ≤60 during the maintenance phase of the general anaesthesia (GA)

Top of page

End point title

The percentage (%) of time of NCI ≤60 during the maintenance phase of the general anaesthesia (GA)

End point description

The primary efficacy endpoint (PEP) was the anaesthetic effect of remimazolam and propofol assessed as percent (%) of time of NCI ≤60 during the maintenance phase of general anaesthesia

End point type

Primary

End point timeframe

During the maintenance phase of the general anaesthesia defined as the time between the first skin incision and the completion of the last skin suture

End point values	Per Protocol Set 1, Remimazolam, Interim Analysis	Per Protocol Set 1, Propofol, Interim Analysis
Number of subjects analysed	165	60
Units: Percentage %
arithmetic mean (standard deviation)	94.6 ( 19.34 )	98.9 ( 5.15 )

Test for non-inferiority

Statistical analysis description

non-inferiority margin pre-specified as 10%, t-test

Comparison groups

Per Protocol Set 1, Remimazolam, Interim Analysis v Per Protocol Set 1, Propofol, Interim Analysis

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

= 0.0003 ^[2]

Method

t-test, 1-sided

Parameter type

Mean difference (final values)

Point estimate

-4.24

Confidence interval

level

97.5%

sides

1-sided

lower limit

-7.48

upper limit

Notes
[1] - Primary confirmatory analysis per definition based on Per Protocol Set 1 at Interim Analysis with missing values over up to 300 seconds imputed by linear regression.
[2] - Non-inferiority of remimazolam to propofol in terms of percent of maintenance time (first skin incision to completion of last skin suture) with Narcotrend index ≤60 was proven.

Secondary: Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Interim Analysis

Top of page

End point title

Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Interim Analysis

End point description

Events were defined as: - MAP dropping below 65 mmHg for 1 minute duration - MAP decrease by more than 20% below the calculated (mean) baseline MAP for 1 minute - MAP decrease by more than 30% below the calculated (mean) baseline MAP for 1 minute - Norepinephrine bolues (0.01 mg) or each time interval of 2 minutes of infusion of norepinephrine to maintain MAP equal to or above 65 mmHg. Due to the interdependency of event types 2 and 3 (decrease by 20% and decrease by 30%) and due to progress in the general scientific debate after finalisation of the trial design, a common factor analysis was performed to elaborate on the statistically and clinically meaningful differences between the treatment groups.

End point type

Secondary

End point timeframe

Start of trial drug (remimazolam or propofol) until 15 minutes after the first skin incision

End point values	Full Analysis Set, Remimazolam, Interim Analysis	Full Analysis Set, Propofol, Interim Analysis
Number of subjects analysed	191	63
Units: total number of events per patient
arithmetic mean (standard deviation)	-0.06 ( 0.580 )	0.17 ( 0.692 )

Wilcoxon rank-sum test

Statistical analysis description

The results were found to not follow normal distribution.

Comparison groups

Full Analysis Set, Remimazolam, Interim Analysis v Full Analysis Set, Propofol, Interim Analysis

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.0247 ^[4]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[3] - Group-sequential design with 1 interim analysis. Alpha split with prespecified type 1 error rate of 0.0193 at interim analysis and 0.0307 at final analysis.
[4] - P-value above pre-specified alpha error at interim analysis of 0.0193

Secondary: Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Final Analysis

Top of page

End point title

Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Final Analysis

End point description

Critical decreases in mean arterial blood pressure (MAP) between start of trial drug (remimazolam or propofol) and 15 minutes after the first skin incision, Final Analysis

End point type

Secondary

End point timeframe

Between start of trial drug (remimazolam or propofol) and 15 minutes after the first skin incision

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	270	95
Units: Events
arithmetic mean (standard deviation)	-0.04 ( 0.529 )	0.13 ( 0.584 )

Wilcoxon rank-sum test

Statistical analysis description

Test for superiority

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

365

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0151 ^[5]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[5] - Actual p-value below pre-specified alpha error of 0.0307

Other pre-specified: Percentage of time of NCI ≤60 and ≥27 during the maintenance phase

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End point title

Percentage of time of NCI ≤60 and ≥27 during the maintenance phase

End point description

Missing Narcotrend Index values up to 300 seconds were imputed by linear regression

End point type

Other pre-specified

End point timeframe

From first skin incision to last skin suture

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis	Per Protocol Set 1, Remimazolam, Final Analysis	Per Protocol Set 1, Propofol, Final Analysis
Number of subjects analysed	270	95	235	92
Units: percent
arithmetic mean (standard deviation)	68.4 ( 31.16 )	78.0 ( 27.88 )	70.1 ( 30.58 )	78.1 ( 28.22 )

Test for difference

Comparison groups

Full Analysis Set, Propofol, Final Analysis v Full Analysis Set, Remimazolam, Final Analysis

Number of subjects included in analysis

365

Analysis specification

Post-hoc

Analysis type

other ^[6]

P-value

= 0.0082 ^[7]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-9.63

Confidence interval

level

95%

sides

2-sided

lower limit

-16.7

upper limit

-2.51

Notes
[6] - Test for difference in means
[7] - The mean time with NCI less than or equal to 60 and greater than or equal to 27 differed between the treatment groups.

Other pre-specified: Percentage of time of NCI <27 during maintenance

Top of page

End point title

Percentage of time of NCI <27 during maintenance

End point description

NCI <27 was regarded as generally not desirable, as indicating anaesthesia being too deep, though standards vary between site.

End point type

Other pre-specified

End point timeframe

Between first skin incision and last skin suture

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis	Per Protocol Set 1, Remimazolam, Final Analysis	Per Protocol Set 1, Propofol, Final Analysis
Number of subjects analysed	270	95	235	92
Units: percent
arithmetic mean (standard deviation)	24.4 ( 29.28 )	21.1 ( 28.12 )	25.3 ( 29.52 )	21.0 ( 28.46 )

Test for difference

Statistical analysis description

Test for difference in means between both treatment groups

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

365

Analysis specification

Post-hoc

Analysis type

other ^[8]

P-value

= 0.3331 ^[9]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

3.35

Confidence interval

level

95%

sides

2-sided

lower limit

-3.45

upper limit

10.15

Notes
[8] - Test for difference in means between both treatment groups
[9] - The means of the treatment groups did not differ from each other.

Other pre-specified: Percentage of patients with NCI ≤60 and ≥27 during 90% of maintenance

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End point title

Percentage of patients with NCI ≤60 and ≥27 during 90% of maintenance

End point description

End point type

Other pre-specified

End point timeframe

Between first skin incision and last skin suture

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis	Per Protocol Set 1, Remimazolam, Final Analysis	Per Protocol Set 1, Propofol, Final Analysis
Number of subjects analysed	270	95	235	92
Units: Patients	94	54	88	53

Test for difference

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

365

Analysis specification

Post-hoc

Analysis type

other ^[10]

P-value

= 0.0002 ^[11]

Method

Chi-squared

Parameter type

percentage

Confidence interval

Notes
[10] - Test for difference
[11] - The percentage of patients with NCI ≤ 60 and ≥27 during at least 90% of the maintenance time differed between the treatment groups.

Other pre-specified: Percentage of patients who were administered rescue sedative medication

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End point title

Percentage of patients who were administered rescue sedative medication

End point description

End point type

Other pre-specified

End point timeframe

Between first skin incision and last skin suture

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis	Per Protocol Set 1, Remimazolam, Final Analysis	Per Protocol Set 1, Propofol, Final Analysis
Number of subjects analysed	270	95	235	92
Units: Patients	27	1	11	1

Test for difference

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

365

Analysis specification

Post-hoc

Analysis type

other ^[12]

P-value

= 0.0009 ^[13]

Method

Chi-squared

Parameter type

percentage

Confidence interval

Notes
[12] - Test for difference
[13] - The treatment groups differed from each other in terms of percentage of patients who received rescue medication during the maintenance period.

Other pre-specified: Intra-operative explicit awareness

Top of page

End point title

Intra-operative explicit awareness

End point description

Occurrence of intra-operative awareness emerging from answers to the Brice questionnaire

End point type

Other pre-specified

End point timeframe

Start of trial drug (remimazolam or propofol) until last skin suture

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	270	95
Units: Patients	0	0

No statistical analyses for this end point

Other pre-specified: Time to loss of consciousness

Top of page

End point title

Time to loss of consciousness

End point description

Time from start of trial drug (remimazolam or propofol) until loss of consciousness, defined as Modified Observer Assessment and Sedation Scale = 0

End point type

Other pre-specified

End point timeframe

Start of trial drug (remimazolam or propofol) until first skin suture

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	268	95
Units: minutes
median (confidence interval 95%)	2.5 (2.5 to 2.8)	3.0 (3.0 to 3.2)

Test for difference

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

363

Analysis specification

Post-hoc

Analysis type

other ^[14]

P-value

= 0.3523 ^[15]

Method

Logrank

Parameter type

Median

Confidence interval

Notes
[14] - Test for difference in median between treatment groups
[15] - The median time from start of the trial drug (remimazolam or propofol) to loss of consciousness did not differ between the treatment groups.

Other pre-specified: Time to loss of palpebral reflex

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End point title

Time to loss of palpebral reflex

End point description

Median time from start of trial drug (remimazolam or propofol) to loss of palpebral reflex

End point type

Other pre-specified

End point timeframe

Start of trial drug (remimazolam or propofol) until first skin incision

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	269	95
Units: minutes
median (confidence interval 95%)	2.8 (2.7 to 3.0)	3.1 (3.0 to 3.5)

Test for difference

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

364

Analysis specification

Post-hoc

Analysis type

other ^[16]

P-value

= 0.1324 ^[17]

Method

Logrank

Parameter type

Median

Confidence interval

Notes
[16] - Test for difference in median between treatment groups
[17] - The median time from start of the trial drug (remimazolam or propofol) to loss of palpebral reflex did not differ between the treatment groups.

Other pre-specified: Time to first Narcotrend Index 60 or less

Top of page

End point title

Time to first Narcotrend Index 60 or less

End point description

Time from start of trial drug (remimazolam or propofol) to first Narcotrend index ≤60

End point type

Other pre-specified

End point timeframe

Start of trial drug (remimazolam or propofol) to first skin incision

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	269	95
Units: minutes
median (confidence interval 95%)	3.2 (2.9 to 3.5)	3.3 (3.1 to 3.5)

Test for difference

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

364

Analysis specification

Post-hoc

Analysis type

other ^[18]

P-value

= 0.0553 ^[19]

Method

Logrank

Parameter type

Median

Confidence interval

Notes
[18] - Test for difference in median between treatment groups
[19] - The median time from start of the trial drug (remimazolam or propofol) to the first Narcotrend Index ≤60 did not differ between the treatment groups.

Other pre-specified: Time to extubation

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End point title

Time to extubation

End point description

Time from stop of trial drug (remimazolam or propofol) to successful, completed extubation

End point type

Other pre-specified

End point timeframe

From stop of trial drug (remimazolam or propofol) to end of follow-up

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	263 ^[20]	95
Units: minutes
median (confidence interval 95%)	12 (11 to 13)	11 (10 to 12)

Notes
[20] - Some subjects did not qualify due to use other sedatives/anaesthetics during the time of interest

Test for difference

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

358

Analysis specification

Post-hoc

Analysis type

other ^[21]

P-value

= 0.0076 ^[22]

Method

Logrank

Parameter type

median

Confidence interval

Notes
[21] - Test for difference in median between treatment groups
[22] - The median time from stop of the trial drug (remimazolam or propofol) differed between the treatment groups. The median time from stop of trial drug to end of extubation was 12 minutes in the Remimazolam group and 11 minutes in the Propofol group.

Other pre-specified: Time to response to verbal command

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End point title

Time to response to verbal command

End point description

Time from stop of administration of the trial drug (remimazolam or propofol) to response to verbal command, Modified Observer Assessment of Alertness and Sedation Scale (MOAA/S) ≥ 4

End point type

Other pre-specified

End point timeframe

From stop of the trial drug (remimazolam or propofol) to end of follow-up

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	257	95
Units: minutes
median (confidence interval 95%)	15 (13 to 17)	12 (10 to 13)

Test for difference

Comparison groups

Full Analysis Set, Propofol, Final Analysis v Full Analysis Set, Remimazolam, Final Analysis

Number of subjects included in analysis

352

Analysis specification

Post-hoc

Analysis type

other ^[23]

P-value

< 0.0001 ^[24]

Method

Logrank

Parameter type

Median

Confidence interval

Notes
[23] - Test for difference in median between treatment groups
[24] - The median time from stop of trial drug (remimazolam or propofol) to response to verbal command differed between the treatment groups.

Other pre-specified: Time to orientation

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End point title

Time to orientation

End point description

Time to orientation to time, place, person and situation

End point type

Other pre-specified

End point timeframe

From stop of trial drug (remimazolam or propofol) until end of follow-up

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	262	95
Units: minutes
median (confidence interval 95%)	54 (47 to 61)	30 (27 to 33)

Test for difference

Statistical analysis description

Test for difference in median between treatment groups

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

357

Analysis specification

Post-hoc

Analysis type

other ^[25]

P-value

< 0.0001 ^[26]

Method

Logrank

Parameter type

Median

Confidence interval

Notes
[25] - Test for difference in median between treatment groups
[26] - The median time from stop of trial drug (remimazolam or propofol) to orientation differed between the treatment groups.

Other pre-specified: Time to Modified Aldrete Score ≥9

Top of page

End point title

Time to Modified Aldrete Score ≥9

End point description

Time from stop of the trial drug (remimazolam or propofol) until the Modified Aldrete Score was 9 or more for the first time

End point type

Other pre-specified

End point timeframe

Time from stop of trial drug (remimazolam or propofol) until end of follow-up

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	260	95
Units: minutes
median (confidence interval 95%)	53 (44 to 58)	37 (28 to 45)

Test for difference

Statistical analysis description

Test for difference in median between the treatment groups

Comparison groups

Full Analysis Set, Remimazolam, Final Analysis v Full Analysis Set, Propofol, Final Analysis

Number of subjects included in analysis

355

Analysis specification

Post-hoc

Analysis type

other ^[27]

P-value

= 0.1205 ^[28]

Method

Logrank

Parameter type

Median

Confidence interval

Notes
[27] - Test for difference in median between treatment groups
[28] - The median time from stop of the trial drug (remimazolam or propofol) to Modified Aldrete Score ≥9 did not differ between the treatment groups.

Other pre-specified: Investigator's overall satisfaction with trial drug

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End point title

Investigator's overall satisfaction with trial drug

End point description

Investigator's overall satisfaction with trial drug (remimazolam or propofol) captured as score between 1 and 10 with 1 representing very dissatisfied and 10 representing very satisfied. Success was assumed if the score was 8, 9 or 10.

End point type

Other pre-specified

End point timeframe

not applicable

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	270	95
Units: Score 1 to 10
Success	149	52

No statistical analyses for this end point

Other pre-specified: Bradycardia events during induction

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End point title

Bradycardia events during induction

End point description

Events of bradycardia were defined as either heart rate below 45 beats per minute over at at least 1 minute, heart rate decrease by >20% below calculated mean baseline heart rate for at least 1 minute, heart rate decrease by >30% below calculated mean baseline heart rate for at least 1 minute, or injections of atropine or glycopyrrolate.

End point type

Other pre-specified

End point timeframe

Between start of trial drug (remimazolam or propofol) and 15 minutes after the first skin incision

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	270	95
Units: mean number of events
arithmetic mean (standard deviation)	26.00 ( 38.947 )	45.95 ( 46.587 )

No statistical analyses for this end point

Other pre-specified: Pain on injection

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End point title

Pain on injection

End point description

Pain on injection was measured using a score from 0 to 10 with 0 representing no pain and 10 representing most severe pain imaginable. Pain was regarded as remarkable when the score was 6 or more.

End point type

Other pre-specified

End point timeframe

Score were to be provided by patient on Day 1, i.e. on the day of the general anaesthesia, after recovery

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	291	118
Units: Score 0 to 10
Remarkable pain, score 6 or more	1	30

No statistical analyses for this end point

Other pre-specified: Delirium assessed by Nu-DESC

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End point title

Delirium assessed by Nu-DESC

End point description

A Nu-DESC score of 2 or more indicates potential delirium

End point type

Other pre-specified

End point timeframe

Nu-DESC total score was to be captured on Day 1, during the recovery period of the general anaestheis

End point values	Full Analysis Set, Remimazolam, Final Analysis	Full Analysis Set, Propofol, Final Analysis
Number of subjects analysed	291	118
Units: Patients with score 2 or more	56	8

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From start of Screening (Day 28 before the start of trial drug administration) until end of Follow-up (Day 2)

Adverse event reporting additional description

Any adverse event reported spontaneously by the patient, discovered on physical examination or other assessment procedures (e.g. laboratory testing or scales such as the Nu-DESC) or uncovered as a result of general questioning by the trial staff is recorded.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Safety Analysis Set, Remimazolam

Reporting group description

All patients who were exposed to any amount of trial drug (remimazolam or propofol), regardless whether assignment to remimazolam or propofol was done by randomization or by pre-defined treatment assignment (first 2 patients of each trial centre, first patient was always assigned to propofol, second patients was always assigned to remimazolam).

Reporting group title

Safety Analysis Set, Propofol

Reporting group description

Serious adverse events	Safety Analysis Set, Remimazolam	Safety Analysis Set, Propofol
Total subjects affected by serious adverse events
subjects affected / exposed	36 / 291 (12.37%)	18 / 118 (15.25%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic cancer metastatic
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Peripheral ischaemia
subjects affected / exposed	1 / 291 (0.34%)	2 / 118 (1.69%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 291 (0.00%)	2 / 118 (1.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Drug effect prolonged
subjects affected / exposed	3 / 291 (1.03%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular stent occlusion
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 291 (0.34%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 291 (0.69%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic artery flow decreased
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram ST segment depression
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Postoperative delirium
subjects affected / exposed	6 / 291 (2.06%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	6 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site occlusion
subjects affected / exposed	2 / 291 (0.69%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural hypertension
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular graft complication
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vasoplegia syndrome
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delayed recovery from anaesthesia
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural hypotension
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	3 / 291 (1.03%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 291 (0.69%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anticholinergic syndrome
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	3 / 291 (1.03%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 291 (0.00%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 291 (0.69%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 291 (0.34%)	1 / 118 (0.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Peritonitis
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 291 (0.34%)	0 / 118 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	6 / 291 (2.06%)	4 / 118 (3.39%)
occurrences causally related to treatment / all	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 291 (0.00%)	2 / 118 (1.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Safety Analysis Set, Remimazolam	Safety Analysis Set, Propofol
Total subjects affected by non serious adverse events
subjects affected / exposed	270 / 291 (92.78%)	114 / 118 (96.61%)
Investigations
Oxygen saturation decreased
Additional description: No results available yet
subjects affected / exposed	28 / 291 (9.62%)	14 / 118 (11.86%)
occurrences all number	28	14
Blood pressure decreased
subjects affected / exposed	35 / 291 (12.03%)	13 / 118 (11.02%)
occurrences all number	296	117
Mean arterial pressure decreased
subjects affected / exposed	21 / 291 (7.22%)	7 / 118 (5.93%)
occurrences all number	21	7
Injury, poisoning and procedural complications
Procedural hypotension
subjects affected / exposed	22 / 291 (7.56%)	11 / 118 (9.32%)
occurrences all number	23	11
Procedural pain
subjects affected / exposed	21 / 291 (7.22%)	11 / 118 (9.32%)
occurrences all number	22	11
Procedural nausea
subjects affected / exposed	20 / 291 (6.87%)	8 / 118 (6.78%)
occurrences all number	20	9
Vascular disorders
Hypotension
subjects affected / exposed	156 / 291 (53.61%)	75 / 118 (63.56%)
occurrences all number	259	159
Hypertension
subjects affected / exposed	24 / 291 (8.25%)	5 / 118 (4.24%)
occurrences all number	24	6
Cardiac disorders
Bradycardia
subjects affected / exposed	52 / 291 (17.87%)	33 / 118 (27.97%)
occurrences all number	63	36
General disorders and administration site conditions
Drug effect prolonged
subjects affected / exposed	21 / 291 (7.22%)	0 / 118 (0.00%)
occurrences all number	21	0
Pain
subjects affected / exposed	16 / 291 (5.50%)	5 / 118 (4.24%)
occurrences all number	17	5
Gastrointestinal disorders
Nausea
subjects affected / exposed	26 / 291 (8.93%)	12 / 118 (10.17%)
occurrences all number	26	12
Vomiting
subjects affected / exposed	15 / 291 (5.15%)	4 / 118 (3.39%)
occurrences all number	16	4
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	21 / 291 (7.22%)	14 / 118 (11.86%)
occurrences all number	21	15

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Jul 2018

Clinical trial amendment 1 included the following specific changes: - Addition of atropine for treatment of bradycardia - Replacement of the 3-minute diagnostic interview for Confusion Assessment Method (3D CAM) by the Nursing Delirium Screening Scale (NuDESC) for the assessment of delirium - Addition of contraceptive requirements as per Clinical Trial Facilitation Group - Change of epidural test dose volume - Addition of prone position to Exclusion Criteria - Screening lab samples must have been taken no more than 7 days before start of trial drug (remimazolam or propofol) - Definition of a non-interventional trial and specifics on previous exposure to drugs under investigation - Dose range of remifentanil infusion widened - Norepinephrine bolus dosing regime clarified - Recommendation on goal-directed therapy altered - Remifentanil allowed for post-operative analgesia - Adverse reaction tables added for remimazolam and propofol - Rationale for body weight independent dosing added (remimazolam only) - Detail on rescue medication use updated - A section on remimazolam and propofol contraindications added - Detail on the method of administration of remimazolam added - 20 minutes post-operative remimazolam: an exception to the rule added (i.e. stopping remimazolam to allow for continued use during transfer to post anaesthesia care unit [PACU] if required, for 20 minutes after last skin suture) - Laboratory samples: modified for clarity - Safety reporting: definitions updated - Co-administration of ringer's lactate and remimazolam not allowed - Flowchart updates and corrections included - Troponin added to the set of lab parameters

04 Dec 2018

- Allergy to lactose of bovine origin was added to the exclusion criteria and contraindications - The NCI corridor to be maintained after reaching an NCI of 60 or less for the first time was changed from between 40 and 60 to between 27 and 60. - A remark was added about the clinical judgement and clinical signs of appropriateness of depth of anaesthesia being relevant in addition to the adherence to the NCI corridor - Instructions on titration of the trial drug (remimazolam or propofol) were amended to avoid changes in dosing that were not necessary. - The dosing schedule for remifentanil was modified from '0.2 ug/kg/min during induction. During maintenance, 0.2 to 0.5 ug/kg/min, for the first 15 minutes after the first skin incision, afterwards 0.05 to 0.5 ug/kg/min' to '0.2 ug/kg/min until intubation. 0.1 to 0.2 ug/kg/min from intubation until 15 minutes after the first skin incision. Afterwards 0.05 to 0.5 ug/kg/min.

24 May 2019

- The end of the Screening Phase was changed from Day-1 to Day 1 prior to arrival at the OR suite. - The Modified Aldrete Score indicating awakening was changed from 10 to 9 or more. - The exclusion criterion regarding drugs that were depressant to the central nervous system was amended to exclude patients with regular use of these drugs.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/22190555
http://www.ncbi.nlm.nih.gov/pubmed/22253270

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Clinical trials

Clinical Trial Results: Phase III confirmatory efficacy and safety trial of remimazolam (CNS7056) compared with propofol for intravenous anaesthesia during elective surgery

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The percentage (%) of time of NCI ≤60 during the maintenance phase of the general anaesthesia (GA)

Primary: The percentage (%) of time of NCI ≤60 during the maintenance phase of the general anaesthesia (GA)

Secondary: Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Interim Analysis

Secondary: Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Interim Analysis

Secondary: Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Final Analysis

Secondary: Critical decreases in mean arterial blood pressure (MAP) between start of trial drug and 15 minutes after the first skin incision, Final Analysis

Other pre-specified: Percentage of time of NCI ≤60 and ≥27 during the maintenance phase

Other pre-specified: Percentage of time of NCI ≤60 and ≥27 during the maintenance phase

Other pre-specified: Percentage of time of NCI <27 during maintenance

Other pre-specified: Percentage of time of NCI <27 during maintenance

Other pre-specified: Percentage of patients with NCI ≤60 and ≥27 during 90% of maintenance

Other pre-specified: Percentage of patients with NCI ≤60 and ≥27 during 90% of maintenance

Other pre-specified: Percentage of patients who were administered rescue sedative medication

Other pre-specified: Percentage of patients who were administered rescue sedative medication

Other pre-specified: Intra-operative explicit awareness

Other pre-specified: Intra-operative explicit awareness

Other pre-specified: Time to loss of consciousness

Other pre-specified: Time to loss of consciousness

Other pre-specified: Time to loss of palpebral reflex

Other pre-specified: Time to loss of palpebral reflex

Other pre-specified: Time to first Narcotrend Index 60 or less

Other pre-specified: Time to first Narcotrend Index 60 or less

Other pre-specified: Time to extubation

Other pre-specified: Time to extubation

Other pre-specified: Time to response to verbal command

Other pre-specified: Time to response to verbal command

Other pre-specified: Time to orientation

Other pre-specified: Time to orientation

Other pre-specified: Time to Modified Aldrete Score ≥9

Other pre-specified: Time to Modified Aldrete Score ≥9

Other pre-specified: Investigator's overall satisfaction with trial drug

Other pre-specified: Investigator's overall satisfaction with trial drug

Other pre-specified: Bradycardia events during induction

Other pre-specified: Bradycardia events during induction

Other pre-specified: Pain on injection

Other pre-specified: Pain on injection

Other pre-specified: Delirium assessed by Nu-DESC

Other pre-specified: Delirium assessed by Nu-DESC

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical Trial Results:
Phase III confirmatory efficacy and safety trial of remimazolam (CNS7056) compared with propofol for intravenous anaesthesia during elective surgery